Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by involuntary, irregularly rhythmic movements of the mouth, tongue, and facial muscles. The upper extremities also may be involved. These movements may be accompanied, to a variable extent, by other involuntary movements and movement disorders. These include rocking, writhing, or twisting movements of the trunk (tardive dystonia), forcible eye closure (blepharospasm), an irresistible impulse to move continually (tardive akathisia), jerking movements of the neck, and disrupted respiratory movements (respiratory dyskinesia). The vast majority of cases of TD are caused by the prolonged use of antipsychotic drugs (neuroleptics). (A relatively small number are caused by the use of other medications, such as metoclopramide, that block dopamine receptors.) TD can manifest, or worsen in severity, after neuroleptic drug therapy is discontinued.
The cumulative incidence of TD in patients exhibiting a first episode of schizophrenia who have undergone a four-year course of neuroleptic treatment is 16.5% (Chakos et al., Arch. Gen. Psychiatry 53:313,1996). The cumulative incidence is substantially higher in older people and in those being treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (manic-depressive illness) (see, e.g., Hayashi et al., Clin Neuropharmacol 19:390, 1996, Jeste et al., Arch. Gen. Psychiatry 52:756, 1995).
TD is associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning. (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol Med. 26:681, 1996; Swartz, Neuropsychobiology 32:115, 1995).
While the pathophysiologic mechanism of tardive dyskinesia is unknown, it has been established that chronic or prolonged administration of typical neuroleptics, all of which act by blocking dopamine receptors results in hypersensitivity or up-regulation of dopamine receptors in the basal ganglia. (see e.g., Andrews, Can J Psych 39:576, 1994; Casey, D. E. in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). The first major hypothesis about the pathophysiology of TD was that TD was the result of this neuronal hypersensitivity to the effects of dopamine. Drugs that increase or enhance dopamine response, especially indirect dopamine agonists, can aggravate the disorder. Many psychiatrists avoid using dopamine agonist anti-Parkinson drugs in neuroleptic therapy because of a concern that increased dopamine will aggravate tardive dyskinesia. (Bezchibnyk-Butler & Remington, Can J. Psych. 39:74, 1994).
Other studies have suggested that irreversible cases of tardive movement disorders may be related to excitotoxic damage to the basal ganglia (Andreasen & Jorgensen, 1994). An acquired deficiency of the inhibitory neurotransmitter GABA has also been implicated in the development of TD (Delfs et al. Experimental Neurol. 133:175-188, 1995).
The physical manifestations of TD can resemble movement disorders associated with degenerative diseases such as Huntington's disease and Parkinson's disease. In particular, patients with Huntington's disease may demonstrate limb movements (chorea) similar to those seen in patients with TD. In addition, the neck, trunk and limb movements of TD may resemble those caused by the "peak-dose dyskinesia" associated with prolonged levodopa treatment of Parkinson's disease.
Recent research suggests that Vitamin E can reduce symptoms of TD modestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri et al. 1994). GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD. (Gardos & Cole, "The Treatment of Tardive Dyskinesias", in Psychopharmacology: The Fourth Generation of Progress, eds. Bloom and Kupfer, pp. 1503-1510, 1995). This same review reports variable benefits associated with other agents including propranolol, clonidine, cholinergic agonists, buspirone and calcium-channel antagonists. However, none of these has become a generally accepted treatment for either the movement or cognitive disorders associated with TD. In co-pending, commonly-owned application Ser. No. 08/861,801, incorporated herein by reference, treatment with memantine, a congener of amantadine and a N-methyl-D-aspartate type (NMDA) receptor blocker as well as a dopamine agonist, has been suggested as an effective treatment of both the movement and cognitive disorders associated with TD.
Acamprosate (calcium N-acetylhomotaurinate) is the calcium salt of a derivative of the amino acid taurine. It is known to be an agonist at GABA receptors. Moreover, it reduces the postsynaptic response of NMDA-type glutamate receptors and reduces calcium influxes through voltage-operated channels. (Wilde & Wagstaff, Drugs 53:1039-53, 1997) Acamprosate is used clinically in the treatment of abstinent alcoholics to reduce or inhibit the craving for alcohol. Animal studies, reported in U.S. Pat. No. 4,355,043 issued to Durlach, showed that acamprosate had an anticonvulsant effect in one specific animal model.
An object of this invention is to develop methods for treating tardive dyskinesia using acamprosate or other homotaurine derivatives.
Another object of this invention to develop methods to treat other hyperkinetic movement disorders (i.e. tardive movement disorders) associated with prolonged exposure to neuroleptic medications or other dopamine receptor blocking agents, using acamprosate or other homotaurine derivatives with similar pharmacologic actions.
Another object of this invention is to develop methods for treating cognitive disorders, including impairments in memory associated with tardive dyskinesia and other movement disorders that are associated with prolonged exposure to neuroleptic medications.
Another object of this invention is to develop methods to treat the peak-dose dyskinesia associated with Parkinson's disease.
More particularly, it is an object of the invention to reduce the severity and duration of involuntary movements associated with tardive dyskinesia.
More particularly, it is the object of this invention to develop methods for improving cognitive function in patients exhibiting TD, specifically to increase memory, span of concentration, and everyday functional performance in activities particularly dependant upon cognition. These improvements in function are measured both subjectively and objectively. The improvement in memory can be demonstrated by standard neuropsychological tests.
Another object of the invention is to develop methods of treating or retarding the onset of tardive dyskinesia in abstinent alcohol abusers who are treated with neuroleptics for concurrent mental disorders, such as bipolar disorder and schizophrenia.